Ipglycermides Novel potent and selective inhibitors of parasitic phosphoglycerate mutase

该项目已从我们的基于目标的分析和筛选策略的化学探针和治疗性铅发现类别中取得进展。 在与H.Suga教授(东京大学)、C.Hoffman教授(波士顿学院)和Scott Lovell教授(UKansas大学)的持续和扩大合作中，ADST实验室利用新的环肽库和亲和力选择和浓缩方法开发了针对致病线虫的这种重要代谢酶的多肽大环。描述该项目初始阶段的工作于2017年发表，进一步阐明异甘油胺与IPGM结合的完整结构-活性关系的工作于2021年发表。 该项目导致了异甘油三胺的发现和表征，这是迄今为止所测试的所有线虫物种中第一种有效和选择性地抑制ipGM的抑制剂类别。我们扩展了这个范例，获得了第一个能够有效抑制包括金黄色葡萄球菌在内的几种原核生物IPGM的酶活性的异甘油三胺。 正在开发一种模式生物线虫系统，以测试膜渗透类似物对生物体生存能力的活性。 从几个共晶体结构揭示的结合位点相互作用为目前正在评估的类似物的设计提供了一般的分子洞察，并在一组iPGM同源基因中进行了评估，最终目的是在目前正在开发的次级细胞和模型生物分析中进行评估。 伊普甘油胺大环肽的化学类型现已扩展到原核感染性生物ipgms 含有异甘油三胺的N-甲基胺产生了更多的蛋白水解性。

This project has advanced from our Target-based Assays and Screening Strategies for Chemical Probe and Therapeutic Lead Discovery category. In continued and expanded collaboration with Prof. H. Suga (U. Tokyo), Prof. C. Hoffman (Boston College) and Scott Lovell (U. Kansas) the ADST laboratory has developed peptide macrocycles targeting this essential metabolic enzyme of the pathogenic nematode using novel cyclic peptide libraries and affinity selection and enrichment approaches. The work describing the initial phase of this project was published in 2017, and further work to elucidate the complete structure-activity relationship of ipglycermide binding to iPGM was published in 2021. This project has resulted in the discovery and characterization of Ipglycermides, the first inhibitor class that potently and selectively inhibits iPGM from all nematodes species thus far tested. We have expanded the paradigm to obtain the 1st ipglycermides capable of potently inhibiting the enzymatic activity of several prokaryotic iPGMs, including S. aureus. A model organism C. elegans systems is being developed to test the activity of membrane permeable analogs on the viability of the organism. The binding site interaction revealed from several co-crystal structures have provided general molecular insights for the design of analogs now being evaluated in across a panel of iPGM orthologs with the eventual aim to evaluate in the secondary cell and model organism assays now under development. Ipglycermide macrocyclic peptide chemotypes have now been extended to prokaryotic infectious organism iPGMs N-methyl amide containing ipglycermides, more proteolytically resistant have been generated.